1. Field of the Invention
The present invention relates to plastic surgical instruments, medical devices, prosthetic cardiovascular implants and implants for hard and soft tissue, contact lenses and the like and methods for improving surfaces thereof.
2. Discussion of the Prior Art
Studies have shown that the surgical implantation of ocular implants such as intraocular lenses (IOL) and the like can result in the loss of significant corneal endothelial tissue unless great care is taken to ensure a lack of contact between the device and the endothelium. Most ocular implants are constructed of hydrophobic polymethylmethacrylate (PMMA) polymers because of their superior optical qualities, resistance to biodegradation and the like. It has been found, however, that PMMA surfaces adhere to endothelial cells upon even casual contact and that separation of the surface therefrom results in a tearing away of the endothelial tissue adhered to the polymer surface. Similar adhesive interactions with other ocular tissues, i.e., the iris, can also cause adverse tissue damage. Other hydrophobic polymers which are used or have been proposed for use in ocular implants (i.e., polypropylene, polyvinylidene fluoride, polycarbonate, polysiloxane) also can adhere to ocular tissue and thereby promote tissue damage.
It is well documented in the prior art that a significant disadvantage inherent in PMMA IOLs resides in the fact that any brief, non-traumatic contact between corneal endothelium and PMMA surfaces results in extensive damage to the endothelium. See Bourne et al, Am. J. Ophthalmol., Vol. 81, pp. 482-485 (1976); Forster et al, Trans. Am. Acad. Ophthalmol. Otolaryngol., Vol. 83, OP-195-OP-203 (1977); Katz et al, Trans. Am. Acad. Ophthalmol. Otolaryngol., Vol. 83, OP-204-OP-212 (1977); Kaufman et al, Science, Vol. 198, pp. 525-527 (1977) and Sugar et al, Arch. Ophthalmol., Vol. 96, pp. 449-450 (1978) for a discussion of the problem associated with implant surface/endothelium contact.
Since it is extremely difficult to avoid any contact between implant surfaces and endothelium during surgical procedures and especially to other sensitive ocular tissues during implant life, i.e., the iris, ciliary sulcus and the like, efforts have been undertaken to modify the PMMA ocular implant surfaces to reduce the tendency thereof to adhere to and damage corneal endothelium.
Ocular implant surfaces have been coated with various hydrophilic polymer solutions or temporary soluble coatings such as methylcellulose, polyvinylpyrrolidone Katz et al, supra, and Knight et al, Chem. Abs., Vol. 92:203547f (1980)! to reduce the degree of adhesion between the implant surfaces and tissue cells. While offering some temporary protection, these methods have not proven entirely satisfactory since such coatings complicate surgery, do not adhere adequately to the implant surfaces, become dislodged or deteriorate after implantation, dissolve away rapidly during or soon after surgery or may produce adverse post-operative complications. Moreover, it is difficult to control the thickness and uniformity of such coatings.
Yalon et al Acta: XXIV, International Congress of Ophthalmology, ed. Paul Henkind (1983)! and Knight et al, supra, have reported attempts to produce protective coatings on PMMA implant surfaces by gamma-radiation induced polymerization of vinylpyrrolidone thereon. Their efforts were not altogether successful, however, since their methods also presented problems in controlling the optical and tissue protective qualities of the coatings. Process conditions and parameters (i.e., monomer concentration solvent, dose and dose rate) were not specified. The resulting coatings were of poor quality and non-uniform mechanical stability.
Gamma-PVP treatment of PTFE has been reported, but under severe process conditions requiring gamma doses above 1 Mrad which are impractical in that both bulk and surface properties of the PTFE are changed Boffa et al, J. Biomed. Mater. Res., Vol. 11, p. 317 (1977)!. Non-aqueous solutions of high monomer concentrations (50% NVP in pyridine) are required at relatively high doses of gamma radiation (1-5 Mrad), resulting in a high degree of grafting, but with extensive changes in the bulk and surface properties of the PTFE since PTFE is readily degraded at gamma doses above 1 Mrad.
In U.S. Pat. No. 4,806,382 issued Feb. 21, 1989, there are described improved methods for producing hydrophilic, gamma-irradiation induced polymerized and chemically grafted coatings on ocular implants constructed of a variety of polymeric materials, which methods overcome the above-noted difficulties and disadvantages.
The invention described in that application is predicated on the discovery of certain process conditions and parameters that produce thin hydrophilic gamma-irradiation induced polymerized and chemically grafted coatings of N-vinyl-pyrrolidone (NVP) PVP!, copolymerized NVP and 2-hydroxyethylmethacrylate (HEMA) P(NVP-HEMA)!, or HEMA PHEMA! and their copolymers, particularly with ionic comonomers on the surfaces of ocular implants constructed of materials including polymethylmethacrylate (PMMA) and of other process conditions and parameters which produce thin gamma-irradiation induced graft PVP, P(NVP-HEMA), PHEMA or copolymer coatings on the surfaces of ocular implant articles constructed of materials including polypropylene (PP), polyvinylidene fluoride (PVDF), polycarbonate (PC) and polysiloxane (PDMSO) or silicone (PSi). The coatings increase the hydrophilicity of the implant surface and minimize adhesion between the surface and sensitive ocular tissues such as corneal endothelium or iris thereby minimizing tissue damage and post-operative complications occasioned by contact between the implant surface and ocular tissue. The coatings produced by the improved method of the invention described in U.S. Pat. No. 4,806,382 are thin and reproducibly uniform. Moreover, they are chemically bound to the surface of the ocular implant and, therefore, far more durable and less subject to removal, degradation or deterioration during or following surgery than the coatings produced by prior art methods.
The improved gamma-irradiation induced graft polymerization of NVP, HEMA or mixtures of NVP and HEMA on ocular implant surfaces comprising PMMA to form optimum PVP, P(NVP-HEMA) or PHEMA graft polymer surface modifications thereon described in U.S. Pat. No. 4,806,382 comprises carrying out the graft polymerization in an aqueous solution under specific combinations of the following conditions:
(a) monomer concentration in the range of from about 0.5 to about 50%, by weight; PA1 (b) total gamma dose in the range of from about 0.01 to about 0.50 Mrad; PA1 (c) gamma dose rate in the range of from about 10 to about 2,500 rads/minute; and PA1 (d) maintaining the molecular weight of the polymer in solution in the range of from about 250,000 to about 5,000,000. PA1 (e) substantially excluding free oxygen from the aqueous graft polymerization solution; PA1 (f) maintaining the thickness of the PVP or P(NVP-HEMA) surface graft in the range of from about 100 .ANG. to about 150 microns; PA1 (g) including a free radical scavenger in the aqueous graft polymerization solution; and PA1 (h) including in the aqueous graft polymerization solution a swelling solvent for PMMA or other polymer substrate surface. PA1 (a) monomer concentration in the range of from about 0.5 to about 50%, by weight; PA1 (b) total gamma dose in the range of from about 0.01 to about 0.50 Mrad; PA1 (c) gamma dose rate in the range of from about 10 to about 2,500 rads/minute; and PA1 (d) maintaining the molecular weight of the polymer in solution in the range of from about 250,000 to about 5,000,000. PA1 (e) substantially excluding free oxygen from the aqueous graft polymerization solution; PA1 (f) maintaining the thickness of the PVP or P(NVP-HEMA) surface graft in the range of from about 100 .ANG. to about 100 microns; PA1 (g) including a free radical scavenger in the aqueous graft polymerization solution; and PA1 (h) including in the aqueous graft polymerization solution a swelling solvent for PMMA or other polymer substrate surface. PA1 (a) Thin, permanent, optically clear (in the case of contact lenses) and uniform graft coatings. The literature generally discloses conditions which produce distortion and degradation of the substrate due to the use of high gamma-irradiation doses (&gt;1 Mrad) and non-aqueous solvent media, and yield thick, cloudy, non-uniform coatings e.g., Chapiro, Radiation Chemistry of Polymeric Systems, John Wiley and Sons, Inc., New York (1962); Henglein et al, Angew. Chem., Vol. 15, p. 461 (1958)!. PA1 (b) Long-term biocompatibility in vivo. PA1 (c) Low contact angle (high wettability) for water or underwater air bubble (less than about 30.degree.). PA1 (d) Non-adherent to tissue (adhesive force to endothelium less than about 150 mg/cm.sup.2). PA1 (e) Non-damaging to endothelium (less than ca. 20% damage for in vitro contact tests). PA1 (f) Graft coating may be measurable by ESCA or FTIR analysis. PA1 (g) Abrasion resistance by sliding (dynamic) friction testing showing no change in wetting (contact angle) and confirming before and after presence of graft coating. PA1 (h) Rapid hydration--change from dry state to wetted lubricous state on immersion in water (within five minutes). PA1 (a) Monomer concentration: Increasing monomer concentration increases polymer molecular weight in the graft solution and reduces contact angle (C.A.), i.e., renders the surface more hydrophilic. For example, in the case of forming PVP coatings on PMMA, in the range of from about 3-15% NVP, the PVP viscosity molecular weight (M.sub.v) increases from 560,000 to 2,700,000 and the PMMA graft C.A. decreases from 29.degree. to 21.degree. at 0.1 Mrad and 309 rads/minute. However, this effect is sensitive to dose rate and total dose. For example, at 1-10% NVP, but at a lower dose rate of 64 rads/minute, the molecular weight increases from 400,000 to 4,590,000 and the C.A. decreases from 49.degree. to 18.degree.. PA1 (b) Dose: In general, increasing total gamma dose increases molecular weight of the polymer and reduces the contact angle. However, an important practical limit exists in that at higher doses, lower dose rates and higher monomer concentrations, reaction media become extremely viscous or form gels which are very difficult to wash and to remove (e.g., about 0.25 Mrad and 10% NVP at 309 rads/minute). PA1 (c) Dose rate: Decreasing the gamma radiation dose rate, generally increases solution polymer M.W., e.g., from 1,150,000 to 5,090,000 at 10% NVP and 0.1 Mrad as dose rate decreases from 1,235 to 49 rads/minute. The C.A. also goes down at lower dose rates, i.e., from 31.degree. to 15.degree.. It is a feature of the present invention that the gamma dose rate may be increased to 10.sup.8 rads/minute which considerably shortens the time required to carry out the process. PA1 (d) Solution Polymer Molecular Weight: The molecular weight may vary widely depending upon process conditions, monomers and radical inhibitors used. Effective grafting with low C.A. may, therefore, be achieved with even low molecular weight solution polymer (M.sub.v as low as 5,000-10,000). However, solution polymer M.sub.v greater than 5,000,000 or gels which form during grafting are generally less practical because of washing problems. PA1 (e) Degassing: Removal of oxygen from the graft solutions by a vacuum and/or an inert gas (e.g., argon purging) can have an important effect: lower total doses are required (practical grafting at less than 0.1 Mrad). Oxygen degassing also has a significant effect on PVP M.sub.w and % conversion of monomer. For example, with degassing, good grafting of PVP on polypropylene (PP) is achieved at 0.05 Mrad and 10% NVP (C.A. 15.degree.). Without degassing, little grafting occurs under these conditions. Oxygen degassing is critical to hydrophilic surface modification grafting where the substrate polymer is PP, PVDF or PDMSO. It has been found that graft polymerization is inefficient when using these materials as substrates in the presence of oxygen. Oxygen degassing is also beneficial for PMMA and PC substrates in that much lower radiation doses (0.01-0.15 Mrad) become effective compared with grafting these polymers in the presence of oxygen. PA1 (f) Graft thickness: Surface grafts less than 100-200 .ANG., although non-adhesive and hydrophilic, are useful, but may exhibit somewhat less mechanical "softness" or compliant gel-like surfaces than thicker coatings for reduced tissue-contact trauma. Graft coatings greater than ca. 300-500 .ANG. (or 0.03-0.05 microns) up to 50 microns or more are probably more desirable for many applications as long as they are smooth, uniform, optically clear for optic surfaces, and quickly hydrated. PA1 (g) Free-Radical Scavengers: Free-radical traps, usually reducing agents such as Cu.sup.+, Fe.sup.+2, ascorbic acid and the like are known to inhibit radical polymerization in solution and thus be effective (especially at high gamma doses, high dose rates and high monomer concentrations) in slowing the onset of solution gelation during grafting. However, under practical grafting conditions, this may result in lower molecular weights, high concentrations of unreacted monomer and broad molecular weight distributions. Use of metal salts may also be objectionable where maximum biocompatibility is critical. PA1 (h) Swelling solvents: The use of substrate polymer solvents in the aqueous monomer grafting solution facilitates swelling and monomer diffusion into the polymer before and during gamma polymerization. Penetration of monomers into the substrate increases graft coating thickness and enhances bonding to the surface. Solvents such as ethyl acetate have been shown to greatly facilitate this process with some substrates such as PMMA. PA1 (a) For PVP grafts on PP, PVDF and PDMSO, or combinations thereof, pre-soak the substrate in NVP monomer at 60.degree. C. for 4 hours followed by graft polymerization in 10% aqueous NVP with about 0.15 Mrad gamma radiation at about 500 rads/minute dose rate, but also as high as 10.sup.8 rads/minute dose rate. PA1 (b) For PVP grafts on PMMA, PP, PVDF and PDMSO, or combinations thereof, pre-soak the substrate in 40% aqueous NVP monomer at about 60.degree. C. for 4 hours followed by graft polymerization in 10% aqueous NVP with about 0.15 Mrad gamma radiation at about 500 rads/minute dose rate, but also as high as 10.sup.8 rads/minute dose rate. PA1 c) For PVP grafts on PMMA, PDMSO and PC, or combinations thereof, pre-soak the substrate in 40% aqueous NVP monomer at about 60.degree. C. for 12 hours followed by graft polymerization in 10% aqueous NVP with about 0.15 Mrad gamma radiation at about 500 rads/minute dose rate, but also as high as 10.sup.8 rads/minute dose rate.
The maintenance of the molecular weight of the polymer in solution at certain values, identified in U.S. Pat. No. 4,806,382 as a critical condition of the method, is not actually a "condition" of the method, but rather, as stated in the specification, a result which is dependent on the reaction conditions employed in carrying out the graft polymerization process. It is, therefore, not appropriate to specify the molecular weight of the polymer in solution as a process "condition" since it is rather an outcome of the reaction conditions used in this invention and may be widely varied depending on specific gamma graft monomer-substrate-process conditions. If a certain set of fixed conditions are employed (namely, monomer, monomer concentration, total gamma dose, gamma dose rate and radical polymerization inhibitors), the molecular weight of the polymer formed in solution will be an output of the process which is dependent upon the values of the above-noted monomer, monomer concentration, total gamma dose, gamma dose rate and radical polymerization inhibitor conditions. For example, in the presence of certain ionic monomers, solvents or radical inhibitors, solution polymerization may be significantly inhibited without sacrificing efficient surface graft polymerization and the resulting solution polymer molecular weight may thereby be relatively low (i.e., as low as 5,000-10,000).
Since the application which matured into U.S. Pat. No. 4,806,382 was filed, the inventors of the subject matter defined therein conducted additional research and unexpectedly found that although relatively low doses of 0.01 to 0.20 Mrad are generally preferred for the compositions of this invention, the process could be conducted at a total gamma dose as low as 0.001 Mrad.
The state of the art prior to the application which matured into U.S. Pat. No. 4,806,382 taught the use of relatively high gamma doses, generally greater than 0.5 Mrad, for gamma polymerization grafting and it was, therefore, surprising to find that surface grafting could be achieved at doses as low as 0.01 Mrad. The achievement of effective grafting at doses as low as 0.001 Mrad is, consequently, an even more unexpected result of the process of this invention. Furthermore, although grafting with monomer concentrations as low as 0.5 wt. % was indicated in prior U.S. Pat. No. 4,806,382, further research has revealed that monomer concentrations as low as 0.1 wt. % may be utilized in some embodiments of the graft process of this invention.
Optimally, the method may also be carried out under one or more of the following conditions:
The improved gamma-irradiation induced graft polymerization of NVP, mixtures of NVP and HEMA or HEMA and other hydrophilic monomers or their copolymers on ocular implant surfaces comprising PP, PVDF, PC or PDMSO to form optimum PVP or P(NVP-HEMA) graft polymer surface grafts thereon may also be carried out under specific combinations of the process parameters as indicated above for PMMA, but also under conditions which involve excluding free oxygen from the polymerization solution for preferred surface modification of these ocular implant polymer substrates.
At the present time, surgical instruments, medical devices, prosthetic implants, contact lenses and the like which are intended for contact with blood or with sensitive tissue surfaces are constructed of materials having the necessary physical properties to enable their use for the intended application; however, they suffer from the disadvantage that due to the generally hydrophobic nature of the blood or tissue contacting surfaces thereof, they exhibit undesired thrombogenic properties and significant damage may occur to fragile or sensitive tissues by adhesion and manipulation or movement on contact with these instruments.
In U.S. Pat. No. 4,961,954, there are described improved methods for producing hydrophilic, gamma-irradiation induced polymerized and chemically grafted coatings on such instruments, devices and the like so constructed of a variety of polymeric materials.
The invention described in the above-noted patent is predicated on the discovery of certain process conditions and parameters that produce thin, hydrophilic, gamma-irradiation polymerized and chemically grafted coatings of N-vinylpyr-rolidone (NVP PVP!), copolymerized NVP and 2-hydroxyethyl-methacrylate (HEMA) P(NVP-HEMA)! or HEMA PHEMA! on the surfaces of articles adapted for contact with living tissue of a human or non-human animal, e.g., surgical instruments, medical devices, prosthetic implants, contact lenses and the like constructed of a wide variety of plastic materials. For purposes of the following description of the invention, the term "tissue" is intended to include blood as well as solid tissue surfaces.
The surface modifications or chemically grafted coatings of the invention increase the hydrophilicity of the article surfaces and minimize adhesion between the surface and sensitive tissues such as blood cells, vascular endothelium, peritoneum, pericardium and the like, thereby minimizing tissue damage and complications occasioned by contact between the article and such tissues. The coatings produced are thin and reproducibly uniform. Moreover, they are chemically bound to the surface of the article and, therefore, are far more durable and less subject to removal, degradation or deterioration during or following utilization of the articles than the coatings produced by prior art methods.
The improved gamma-irradiation induced graft polymerization of NVP, HEMA or mixtures of NVP and HEMA on plastic article surfaces to form optimum PVP, P(NVP-HEMA) or PHEMA graft polymer surface modifications thereon described in U.S. Pat. No. 4,961,954 comprises carrying out the graft polymerization in an aqueous solution under specific combinations of the following conditions:
Optimally, the method may also be carried out under one or more of the following conditions:
The invention described in U.S. Pat. No. 5,100,689 relates to plastic articles and methods for their manufacture wherein lower dosages are employed and the manufacture of molecular weight is not a "condition" of the process.
The invention described in U.S. Pat. No. 5,094,876 relates to plastic articles and methods for their manufacture wherein the article surface is first pre-soaked in a solution comprising the monomer prior to graft polymerizing the monomer onto the surface.
It is an object of the present invention to provide a still further improved method for producing hydrophilic coatings on the surfaces of such articles, as well as the articles produced by the improved method.